Treatment Of Painful Diabetic Neuropathy

Under this section the many different approaches to the management of symptoms in those with distal sensory neuropathy will be considered. First, the role of blood glucose control in the prevention and management of painful neuropathy will be discussed followed by a description of the various pharmacological treatments that have been proposed. This section will be divided into those purely symptomatic treatments and those symptoms that target the underlying pathogenesis of neuropathy and might in addition be useful for symptoms. Finally, a number of varied nonpharmacological treatments will be discussed.

Glycemic Control and Painful Diabetic Neuropathy

A number of studies have confirmed the major contribution of prolonged hyperglycemia in the pathogenesis of neuropathy and neuropathic pain (30-33). More recent studies in patients with idiopathic painful neuropathies further support the relationship between hyperglycemia and painful neuropathy. In the study of Singleton et al. (34), impaired glucose tolerance was more common in patients with idiopathic painful neuropathy than the general population. Thus, achieving near normoglycemia should be the primary aim in both the prevention of and the first step in the management of generalized peripheral neuropathy.

A number of small open-label uncontrolled studies have suggested that achieving stable near-normoglycemia is helpful in the management of painful neuropathic symptoms. In one such study (35), patients with painful neuropathy were treated with continuous subcutaneous insulin infusion for a period of 4 months. As well as resulting in the relief of neuropathic pain, improvements were also noted in quantitative measures of nerve function. Improvement of blood glucose control in this study was assessed by glycated hemoglobin as well as by regular home blood glucose monitoring. The fact that blood glucose flux was reduced in this early study might explain the symptomatic benefits of this treatment in light of more recent observations (33). In this latter study, Oyibo et al. compared patients with painful and painless neuropathy: those with painful symptoms had poorer control, more excursions to hyper and hypoglycemic levels and greater blood glucose flux as assessed by a number of measures. It therefore appears that the stability of glycemic control is equally important as the level of achieved control. It might be that biochemical changes associated with blood glucose flux result in spontaneous firing in nociceptive afferent fibres of diseased sensory neurones. Despite the lack of appropriately designed controlled trials in this area, generally, it is accepted that intensive diabetes therapy aimed at stable near-normoglycemia should be the first step in the treatment of any form of diabetic neuropathy.

Disease-Modifying Treatments

A number of agents aimed at correcting the underlying pathogenesis of diabetic neuropathy are currently under investigation, but none is licensed for use in the United States by the Food and Drug Administration (FDA).

Aldose Reductase Inhibitors

As discussed in Chapter 18, the aldose reductase inhibitors block the rate-limiting enzyme, aldose reductase, in the polyol pathway. Numerous aldose reductase inhibitors have been studied for the last 20 years in the management of neuropathy, but with the exception of epalrestat, which is marketed in Japan, presently none is available in any country. Of the many published studies, symptomatic relief was reported in a large multicenter study using the now withdrawn drug tolrestat (36), and pain relief was also reported with epalrestat in a 12-week controlled study (37).

a-Lipoic Acid

There is accumulating evidence to support the role of oxidative stress in the pathogenesis of neuropathy. Studies with the antioxidant a-lipoic acid have provided evidence of potential efficacy for this agent which might well be beneficial both for neuropathic symptom relief, and for modifying the natural history of neuropathy (38,39).

PKC-$ Inhibition

Preliminary data suggest that treatment with the PKC-P inhibitor, Ruboxistaurin, might ameliorate some of the symptoms of diabetic neuropathy (40).

A number of other agents are currently under investigation as reported in recent reviews (6,41).

Symptomatic Pharmacological Treatment of Painful Neuropathy

This section will discuss the pharmacological management of painful neuropathic symptoms. Most of the pharmacological interventions described here have no effect on the natural history of neuropathy which is one of the progressive loss of nerve function. Before considering pharmacological treatment, the initial approach to the management of a patient with symptomatic neuropathy is summarized in Table 4. A large number of therapeutic agents have been used in the management of painful symptoms: some of the more commonly used ones are listed in Table 5. Although some have advocated the use of nonsteroidal, anti-inflammatory drugs as the first treatment for neuropathy, there is little evidence to support their use. Moreover, these agents should be used with caution in neuropathic patients with diabetes many of whom will have renal impairment as a consequence of nephropathy, a contra indication to nonsteroidal drug usage in most cases.

Tricyclic Drugs

Several randomized clinical trials have supported the use of these agents in the management of neuropathic pain. Putative mechanisms by which these drugs relieve pain include inhibition of norepinephrine and/or serotonin reuptake at synapses of central descending pain control systems and more recently, the antagonism of N-methyl-D-aspartate receptors, which mediate hyperalgesia and allodynia (42). Most experience has been achieved with amitriptyline and imipramine. The dosage of both of these agents required for symptomatic relief is similar (25-150 mg daily), although in older patients it can be useful to start at 10 mg daily. To avoid undue drowsiness, the dose can be taken once daily usually in the evening or bedtime. The usefulness of these agents in neuropathic pain was confirmed in the systematic review performed by McQuay et al. (43). However, the major problem with these agents remains the frequency of side